Absorbable polyurethanes and methods of use thereof

ABSTRACT

Disclosed are novel bioabsorbable and biodegradable monomer compounds, bioabsorbable and biodegradable polymers therefrom, and methods of making such monomers and polymers, which are useful in pharmaceutical delivery systems, tissue engineering applications, tissue adhesives products, implantable medical devices, foams and reticulated foams for wound healing and drug delivery, bone hemostats and bone void fillers, adhesion prevention barriers, meshes, filters, stents, medical device coatings, pharmaceutical drug formulations, consumer product and cosmetic and pharmaceutical packaging, apparel, infusion devices, blood collection tubes and devices, other medical tubes, skin care products, and transdermal drug delivery materials.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority under 35 U.S.C.§119(e) of Provisional Application Ser. No. 61/422,447, filed on Dec.13, 2010, the entire disclosure of which is incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates to the discovery of a new class ofbioabsorbable and biodegradable polyurethanes, polyester urethanes andpolyamides, their respective monomeric units and intermediates for thepreparation thereof. The resultant absorbable polymers are useful fordrug delivery matrices, therapeutic compositions, tissue engineering,tissue adhesives, adhesion prevention, and other implantable medicaldevices. Further, the absorbable polymers of the present inventionprovide a controllable degradation profile.

BACKGROUND OF THE INVENTION

Biodegradable polymers have become increasingly important for a varietyof biomedical applications including tissue engineering scaffolds,surgical adhesives, sutures, medical device coatings and drug deliverymatrices, etc.

Isocyanate-based adhesive/sealant compositions are known. For example,U.S. Pat. Nos. 6,894,140; 5,173,301; 4,994,542; and 4,740,534, providedisclosure of such compositions, the disclosures of all of which areincorporated herein by reference in their entirety.

However, the prior art compositions suffer from a number of shortcomingsincluding a slow rate of degradation, and potential toxicity problemsdue to their reduced degradability.

BRIEF SUMMARY OF THE INVENTION

The present invention overcomes the problems that are characteristic ofthe prior art polymeric moieties. It is the object of the presentinvention to provide novel materials and methods of making suchmaterials which would ultimately be useful for drug delivery, tissueengineering, tissue adhesives, adhesion prevention and other implantablemedical devices.

In one aspect of the present invention, novel aromatic amine-containingmonomeric units are disclosed. Another embodiment is directed tobioabsorbable and biodegradable polyamides containing repeating units,including the presently disclosed novel aromatic amine-containingmonomeric units. In another embodiment of the invention, novel methodsfor preparing such biodegradable and biocompatible polyamides, theirrespective prepolymers, intermediates, and compositions thereof aredisclosed. In yet another embodiment of the present invention, novelbiodegradable and biocompatible polymers having a controllabledegradation profile are disclosed, for medicinal and therapeutic uses,such as tissue engineering.

In another aspect of the present invention, novel biodegradable andbiocompatible aromatic diisocyanates are disclosed. In anotherembodiment bioabsorbable and biodegradable polyurethanes andpolyurethane esters containing repeating units having the structure ofthe disclosed aromatic diisocyanate-containing monomeric units aredisclosed. In another embodiment of the present invention, novel methodsfor preparing such biodegradable and biocompatible polyurethanes andpolyurethane esters, their respective prepolymers, intermediates, andcompositions thereof are disclosed. In another embodiment of the presentinvention, novel biodegradable and biocompatible polymers are disclosed,for medicinal and therapeutic uses, for example, without limitation, insuch fields as tissue engineering, reticulated foams for wound healingand drug deliver, bone hemostats and bone fillers.

In a further aspect of the present invention, novel biodegradable andbiocompatible aliphatic and cyclic aliphatic diisocyanates aredisclosed. Another embodiment is directed to bioabsorbable andbiodegradable polyurethane and polyurethane esters containing repeatingunits having the structure of the disclosed aliphatic and cyclicaliphatic diisocyanate-containing monomeric units. In another embodimentof the present invention, novel methods for preparing such biodegradableand biocompatible aliphatic polyurethanes and polyurethane esters, theirrespective prepolymers, intermediates, and compositions thereof aredisclosed. In another embodiment of the present invention, the novelbiodegradable and biocompatible polymers are directed to medicinal andtherapeutic uses, including but not limited to tissue engineering,reticulated foams for wound healing and drug delivery, bone hemostatsand bone fillers.

In another embodiment, the present invention is directed to theapplication of novel hydrolysable isocyanates, amines, biodegradable andbiocompatible polyurethanes and polyamides described in the presentpatent application, optionally in combination with those described inpatents/patent publications U.S. Pat. No. 7,772,352, US 2010/0260702 A1,US 2009/0292029 A1, US 2009/0082540, US 2006/0288547 A1, EP 1937182 B1,EP 2298235 A1, EP 1937182 A4, EP 1937182 A2, and WO 27030464 A2, all ofwhich have been assigned to Bezwada Biomedical, and U.S. Pat. No.4,829,099 assigned to Fuller, et al., for use in medicinal, medicaldevice, therapeutic, consumer product and cosmetic applicationsincluding but not limited to tissue engineering, foams (including butnot limited to reticulated foams, lyophilized foams and regular foams)for wound healing and drug delivery, bone hemostats and bone fillers,tissue adhesive and sealants, adhesion prevention barriers, meshes,filters, bone void fillers, controlled drug delivery, stents, medicaldevice coatings, pharmaceutical drug formulations, medical device,cosmetic and pharmaceutical packaging, apparels, infusion devices, bloodcollection tubes and devices, tubes, skin care and transdermal drugdelivery. The entire disclosures of all of the above-cited patents andpatent publications are incorporated by reference herein.

In another embodiment, the present invention is directed to absorbablepolyurethane foams with open and closed cell structures, including butnot limited to reticulated foams, foams with vertical channels,architecturally gradient foams, trans-compositional foams andtrans-structural foams and the process of preparing these absorbablefoams using the novel hydrolysable isocyanates, amines, biodegradableand biocompatible polyurethanes described in the present patentapplication, optionally in combination with those described inpatents/patent publications U.S. Pat. No. 7,772,352, US 2010/0260702 A1,US 2009/0292029 A1, US 2009/0082540, US 2006/0288547 A1, EP 1937182 B1,EP 2298235 A1, EP 1937182 A4, EP 1937182 A2, and WO 27030464 A2, all ofwhich are assigned to Bezwada Biomedical, and U.S. Pat. No. 4,829,099,assigned to Fuller, et al., via lyophilization wherein the absorbablepolyurethane polymers and/or blends thereof are dissolved in a suitablesolvent such as, without limitation, dioxane, N-methylpyrrolidone,dichloromethane and/or mixtures thereof, to form a homogeneous solutionwhich is subjected to a lyophilization process comprising a solution ofa bioabsorbable elastomer in a solvent which is substantially, but notnecessarily completely, solidified, then the solvent is removed fromthat which is lyophilized under reduced pressure to form a foam. Theentire disclosures of all of the above-cited patents and patentpublications are incorporated by reference herein.

In another embodiment, isocyanates of the present invention provide atrue reticulated, flexible, resilient, bioabsorbable elastomeric matrix,suitable for implantation and having sufficient porosity to encouragecellular ingrowth and proliferation in vivo. The present invention alsoprovides a polymerization process for preparing an absorbablereticulated elastomeric matrix, the process comprising the steps of:

(1) admixing

-   -   a) a polyol component,    -   b) an isocyanate component,    -   c) a blowing agent,    -   d) optionally, a crosslinking agent,    -   e) optionally, a chain extender,    -   f) optionally, one or more catalysts,    -   g) optionally, one or more cell openers,    -   h) optionally, a surfactant, and    -   i) optionally, a viscosity modifier;        to provide a crosslinked elastomeric matrix, and

(2) reticulating the elastomeric matrix by a reticulation process toprovide the reticulated elastomeric matrix.

The ingredients are present in quantities and the elastomeric matrix isprepared under conditions so as to:

(i) provide a crosslinked resiliently-compressible bioabsorbableelastomeric matrix,

(ii) control formation of biologically undesirable residues, and (iii)reticulate the foam by a reticulation process,

to provide the reticulated elastomeric matrix.

In another embodiment, the invention is directed to a lyophilizationprocess for preparing a reticulated elastomeric matrix comprisinglyophilizing a flowable polymeric material. In another embodiment, thepolymeric material comprises a solution of a solvent-solublebioabsorbable elastomer in a solvent. In another embodiment, theflowable polymeric material is subjected to a lyophilization processcomprising solidifying the flowable polymeric material to form a solid,e.g., by cooling a solution, then removing the non-polymeric material,e.g., by evaporating the solvent from the solid under reduced pressure,to provide an at least partially reticulated elastomeric matrix. Inanother embodiment, a solution of a bioabsorbable elastomer in a solventis substantially, but not necessarily completely, solidified, then thesolvent is evaporated from that material to provide an at leastpartially reticulated elastomeric matrix. In another embodiment, thetemperature to which the solution is cooled is below the freezingtemperature of the solution. In another embodiment, the temperature towhich the solution is cooled is above the apparent glass transitiontemperature of the solid and below the freezing temperature of thesolution.

In another embodiment, the invention is directed to a lyophilizationprocess for producing an elastomeric matrix having a reticulatedstructure, the process comprising the steps of:

a) forming a solution comprising a solvent-soluble bioabsorbableelastomer in a solvent;

b) at least partially solidifying the solution to form a solid,optionally by cooling the solution; and

c) removing the non-polymeric material, optionally by evaporating thesolvent from the solid under reduced pressure, to provide an at leastpartially reticulated elastomeric matrix comprising the elastomer.

Another embodiment of the invention is directed to a process forpreparing a reticulated composite elastomeric implantable device forimplantation into a patient, the process comprising surface coating orendoporously coating a bioabsorbable reticulated elastomeric matrix witha coating material selected to encourage cellular ingrowth andproliferation. The coating material can, for example, comprise a foamedcoating of bioabsorbable polyurethane, optionally, collagen,fibronectin, elastin, hyaluronic acid or a mixture thereof.Alternatively, the coating comprises bioabsorbable polyurethane and aninorganic component.

Another object of the present invention is to provide novel safe,biocompatible and bioabsorbable aromatic isocyanate-based adhesives.More particularly, such adhesives are metabolically-acceptable surgicaladhesives and have controllable degradation profiles. In yet anotheraspect of the present invention, methods for closing wounds in livingtissue by use of novel, metabolically-acceptable surgical adhesiveshaving low toxicity are disclosed.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides new classes of amines, isocyanates andbioabsorbable urethanes, aromatic amides and esterurethane compounds andtheir respective polymerized moieties, polyurethanes, polyamides andpolyesterurethanes. The resultant absorbable polymers are useful fordrug delivery as matrices, fillers, coatings, etc; tissue engineeringcomplexes and scaffoldings; tissue adhesives, foams, includingreticulated foams, adhesion prevention matrices and other implantablemedical devices. In addition these absorbable polymers are characterizedby having a controllable degradation profile.

The term “bioabsorbable” is defined as readily reacting or enzymaticallydegrading upon exposure to bodily tissue for a relatively short periodof time, thus providing a significant loss of the original material inthat short time period. Complete bioabsorption should take place withintwelve months, although preferably within three to nine months.Preferably, bioabsorption is complete within nine months, and mostpreferably within six months. Therefore, the polymers of the inventioncan be fabricated into medical and surgical devices, foams,bioadhesives, coatings, etc., which are useful for a vast array ofapplications requiring complete absorption within the relatively shorttime periods as defined above.

The biological properties of the bioabsorbable polymers of thisinvention used to form the device or part thereof, as measured by itsabsorption rate and its breaking strength retention in vivo (BSR), canbe adjusted to suit the needs of the particular application for whichthe fabricated medical device or component is intended. Those ofordinary skill in the art can appreciate that modifications in theratios of the specific components will affect the degradation rate.

For purposes of defining the scope of this invention, the term“elastomer” is defined as a material which at room temperature can bestretched repeatedly to at least twice its original length and, uponimmediate release of the stress, will return with force to itsapproximate original length.

The term “prepolymer” is defined as a low molecular weight polymerusually an intermediate between that of the monomer and the finalpolymer that is capable of further polymerization.

The term “monomeric unit” is defined as a small molecule that canchemically react with other monomers to form a polymer. The term“polymer” is defined as a molecule that is formed by joining repeatingmonomeric units. The polymers of the present invention can be, withoutlimitation, linear, branced, star or comb polymers.

In the preferred embodiments of this invention, the polymer from which amedical device or a component of the device is formed exhibits a percentelongation greater than about 200, preferably greater than about 500. Itwill also exhibit a modulus (Young's Modulus) of less than about 40,000psi, preferably less than about 20,000 psi. These properties, whichmeasure the degree of elasticity of the bioabsorbable elastomer, areachieved while maintaining a tensile strength greater than about 500psi, preferably greater than about 1,000 psi, and a tear strength ofgreater than about 50 lbs/inch, preferably greater than about 80lbs/inch

Generally the functionality of the aromatic monomers is selected fromamine- and/or carboxylic acid-containing phenols, such as amino phenolsand amino salicylic acids, and from amino benzoic acids, as summarizedbelow. Glycolic acid is used as a functionalization moiety for purposesof illustration.

Precursors of the Compounds and Monomeric Units

Glycolic acid and lactic acid are known as alpha-hydroxy acids (AHAs)and are present in fruits and other foods. The chemical formula ofglycolic acid is HOCH₂COOH. This compound is biodegradable. Whenglycolic acid is heated it readily loses water by self-esterification toform polyglycolic acid. Glycolic acid can function as both an acid andan alcohol. This dual functionality leads to a variety of chemicalreactions and valuable physical properties. Many surgical devices aremade from polyglycolic acid. The process of attaching a glycolic acidmoiety to a phenolic compound is defined as glycolation.

Lactic acid is a fermentation product of lactose. It is present in sourmilk, koumiss, leban, yogurt, and cottage cheese. Lactic acid is alsoproduced in the muscles during intense activity. Many surgical andorthopedic devices are made from polylactic acid. The esters of lacticacid are useful as emulsifying agents in baking foods; examples includestearoyl-2-lactylate, glyceryl lactostearate, and glyceryllactopalmitate. The process of attaching a lactic acid moiety to aphenolic compound is defined as lactolation.

Epsilon-caprolactone is a reactive cyclic monomer, and the polymersderived therefrom are useful for tailoring specialty polyols andhydroxy-functional polymer resins with enhanced flexibility. The monomerpolymerizes under mild conditions to give low viscosity productssuperior to conventional aliphatic polyesters. Copolymers ofcaprolactone with glycolide and lactide exhibit unique physical andbiological properties as well as different hydrolysis profiles based onthe composition of the monomers. The process of attaching an open chain8-caprolactone moiety to a phenolic compound is defined as caprolation.

p-Dioxanone (1,4-dioxan-2-one) is a cyclic monomer, and polymers aremade therefrom via ring opening polymerization. Polyesters derived fromthis monomer are used in making absorbable surgical devices with alonger absorption profile (slower hydrolysis) compared to polyglycolicacid. The absorbable surgical devices made from 1,4-dioxan-2-one haveproved to be biologically safe, and biocompatible. The process ofattaching an open chain p-dioxanone moiety to a phenolic compound isdefined as dioxonation.

Many examples of the phenolic amino acids reacted with the abovefunctionalization moieties have been shown to be safe and biocompatible.Embodiments of the new functionalized phenolics have controllablehydrolysis profiles, improved bioavailability, improved efficacy andenhanced functionality. The disclosed difunctional compounds can readilypolymerize into biodegradable polyesters, polyester amides,polyurethanes, polydiamides, and polyanhydrides, which are useful formany applications, including biomedical applications, foodstuffs,nutritional supplements, cosmetics, medicaments, coatings and othersreadily apparent to one skilled in the art.

Monomeric Units/Repeating Compounds

At least one aspect of the present invention focuses on novel compoundsand monomeric units that can be used to form the backbone of a polymer.Accordingly, one aspect of the present invention is directed tocompounds comprising at least one unit selected from the groupconsisting of formulas (1)-(15):

wherein each X represents a member independently selected from the groupconsisting of:—CH₂COO— (glycolic acid moiety);—CH(CH₃)COO— (lactic acid moiety);—CH₂CH₂OCH₂COO— (dioxanone moiety);—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);—(CH₂)_(y)COO— where y is one of the numbers 2,3,4 and 6-24 inclusive;and—(CH₂CH₂O)_(z)′CH₂COO— where z′ is an integer between 2 and 24,inclusive;each X′ represents a member independently selected from the groupconsisting of:—OOCCH₂— (glycolic acid moiety);—OOC(CH₃)CH— (lactic acid moiety);—OOCCH₂OCH₂CH₂— (dioxanone moiety);—OOCCH₂CH₂CH₂CH₂CH₂— (caprolactone moiety);—OOC(CH₂)y- where y is one of the numbers 2,3,4 and 6-24 inclusive; and—OOCCH₂(OCH₂CH₂)z′- where z′ is an integer between 2 and 24, inclusive;each X″ represents a member independently selected from the groupconsisting of:—OCH₂CO— (glycolic acid moiety);—OCH(CH₃)CO— (lactic acid moiety);—OCH₂CH₂OCH₂CO— (dioxanone moiety);—OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone moiety);—O(CH₂)_(y)CO— where y is one of the numbers 2,3,4 and 6-24 inclusive;and—O(CH₂CH₂O)_(z)′CH₂CO— where z′ is an integer between 2 and 24,inclusive;each Y represents a member independently selected from the groupconsisting of:—COCH₂O— (glycolic ester moiety);—COCH(CH₃)O— (lactic ester moiety);—COCH₂OCH₂CH₂O— (dioxanone ester moiety);—COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);—CO(CH₂)_(m)O— where m is an integer between 2-4 and 6-24 inclusive; and—COCH₂O(CH₂CH₂O)_(n)— where n is an integer between 2 and 24, inclusive;each Y′ represents a member independently selected from the groupconsisting of:—OCH₂OC— (glycolic ester moiety);—O(CH₃)CHOC— (lactic ester moiety);—OCH₂CH₂OCH₂OC— (dioxanone ester moiety);—OCH₂CH₂CH₂CH₂CH₂OC— (caprolactone ester moiety);—O(CH₂)_(m)OC— where m is an integer between 2-4 and 6-24 inclusive; and—(OCH₂CH₂)—OCH₂OC— where n is an integer between 2 and 24 inclusive;wherein Z is —O— or —S— or —NH—;

wherein R is an alkylene, alkenylene or alkynylene group which may bestraight-chained or branched, and can optionally contain one or moreoxygen atoms, sulfur atoms, ester groups, aromatic groups or halogenatoms. The alkylene, alkenylene or alkynylene group may also optionallybe cyclic, represented by 1,4-cyclohexylidine orcyclohexane-1,4-methylene (—CH₂c-C₆H₁₀—CH₂—), or the corresponding 1,2-or 1,3-isomers, for example, and optionally containing the above groups.Further, R may be phenylene or 1,4-xylylene (—CH₂—C₆H₄—CH₂—), or thecorresponding 1,2- or 1,3-isomers, for example, optionally containingthe above groups. R can also be an organic moiety derived from alkyl,benzyl, ethylene glycol, organic ether, carboxylic acid, dicarboxylicacid, or substituted or thio derivatives thereof, carrying one, two orthree free valences in the form of mono-, di- or tri-valent radicals,including but not limited to methylene (—CH₂—), ethylene (—CH2CH2-),propylene (—CH2CH2CH2-), vinylene (—CH═CH—), propenylene (—CH═CHCH2-),and the like. In yet another embodiment, R is derived from a polyol,alkylene glycol, ethylene glycol, diethylene glycol, triethylene glycol,polyethylene glycol (polyethyl ether), diethyl ether, or optionallysubstituted analogs thereof. In yet another embodiment, R is a groupderived from a diacid, including but not limited to succinic acid,adipic acid, malonic acid, diglycolic acid, or optionally substitutedderivatives thereof. In still another embodiment R may be abioabsorbable, biodegradable, and/or di-, tri- or multi-valant radicalcontaining at least one oxygen, sulfur or halogen atom; where theR-groups are optionally substituted with alkyl, alkoxy and/or halogen.

Further, the aromatic substituents, Rn, represent one or more moietiesselected from the group consisting of H, alkoxy, phenoxy, benzyloxy,formyl (—CHO), halogen, carboxylic acid and —NO₂, which are attacheddirectly to an aromatic ring, or indirectly via an alkylene chain toform a substituted aromatic moiety. Preferably the alkylene chaincontains 1-24 carbon atoms, more preferably 1-12 carbon atoms, stillmore preferably 1-6 carbon atoms, and most preferably 1-3 carbon atoms.The alkylene chain can be linear or branched. The substituents Rn can beselected such that the precursors are derived from amine- and/orcarboxylic acid-containing phenols, including but not limited to aminophenols (ortho-, meta- or para-) and amino salicylic acids (ortho-,meta- or para-), and can also be derived from amino benzoic acids(ortho-, meta- or para-).

A further aspect of the invention is directed to monomers wherein theisocyanate groups are replaced with isothiocyanates; and polymersproduced therefrom. Specifically, this aspect of the invention isdirected to isothiocyanate analogs of (1)-(15), above.

In one aspect of the present invention, novel biodegradable andbiocompatible aliphatic and cyclic aliphatic diisocyanate-based monomersare disclosed. Preferred cyclic aliphatic diisocyanate-based monomersare the cyclohexane-containing compounds (8)-(15), which are related totheir aromatic counterparts (1)-(7) formally by reduction of the benzenerings to cyclohexane rings. The polymers prepared from such saturatedmonomers have beneficially reduced color, improved transparency and arenon-yellowing.

In a more preferred embodiment, in the structures (1)-(15), X isselected from the group consisting of:

—CH₂COO— (glycolic acid moiety);—CH(CH₃)COO— (lactic acid moiety);—CH₂CH₂OCH₂COO— (dioxanone moiety);—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);and mixtures thereof;

X′ is selected from the group consisting of:

—OOCCH₂— (glycolic acid moiety);—OOC(CH₃)CH— (lactic acid moiety);—OOCCH₂OCH₂CH₂— (dioxanone moiety); and—OOCCH₂CH₂CH₂CH₂CH₂— (caprolactone moiety);

X″ is selected from the group consisting of:

—OCH₂CO— (glycolic acid moiety);—OCH(CH₃)CO— (lactic acid moiety);—OCH₂CH₂OCH₂CO— (dioxanone moiety); and—OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone moiety);

Y is selected from the group consisting of:

—COCH₂O— (glycolic ester moiety);—COCH(CH₃)O— (lactic ester moiety);—COCH₂OCH₂CH₂O— (dioxanone ester moiety); and—COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);

and

Y′ is selected from the group consisting of:—OCH₂CO— (glycolic ester moiety);—O(CH₃)CHCO— (lactic ester moiety);—OCH₂CH₂OCH₂CO— (dioxanone ester moiety); and—OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety);wherein each R is a straight-chained, branched or cyclic alkylene groupcontaining 1-24 carbon atoms, optionally containing one or more oxygenatoms, sulfur atoms, ester groups, halogen atoms, or aromatic groups.each p is independently an integer between 0 and 4, inclusive;

Z is O or S or NH;

andRn represents one or more members selected from the group consisting ofH, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid and —NO₂, andRn is attached directly to the aromatic rings or attached through analkylene chain.

Another aspect of the present invention focus on absorbablepolyurethanes derived from at least one unit selected from the groupconsisting of formulas (1)-(15).

Another aspect of the present invention comprises a tissue adhesivecomposition comprising at least one monomer selected from the groupconsisting of formulas (1)-(15).

Another aspect of the present invention is directed to the preparationabsorbable polyamide, polyester amides and polyureas containingcompounds having at least one unit selected from the group consisting offormulas (16)-(30).

wherein each X, X′, X″, Y, Y′, y, n, z′, Rn and R are as defined above.

Preferred cyclic aliphatic diamine-based monomers are thecyclohexane-containing compounds (23)-(30), which are related to theiraromatic counterparts (16)-(22) formally by reduction of the benzenerings to cyclohexane rings. As for the corresponding cycloaliphaticdiisocyanate monomers, the polymers prepared from such saturated diaminemonomers have beneficially reduced color, improved transparency and arenon-yellowing.

Another aspect of the present invention is directed to methods ofpreparing diamines and diisocyanates containing only monomeric unitscontaining (X)p, where p is 1, and which contain at least one compoundhaving formula (16), (17), (1), or (2):

wherein each X, and Rn are as defined above.

Polymeric Moieties and Methods of Preparation Thereof

Processes for preparing polymers of the invention are provided asfurther embodiments of the invention and are illustrated by thefollowing general methods:

Polyamides can be prepared by self condensation or by reacting withanother amino acid (HOOC—R—NH₂).

Again, polyamides can be prepared by self condensation or by reactingwith a different amino acid (HOOC—R—NH₂).

The monomer compounds of the invention can be used to polymerizebiocompatible, biodegradable polyurethanes, polyester urethanes, andpolyamides useful in a variety of applications where delivery of abiologically active compound is desired. Examples of such applicationsinclude, but are not limited to, medical, dental and cosmetic uses.

In another embodiment, copolymers of the absorbable polymers of thisinvention can be prepared by preparing a prepolymer under meltpoly-condensation conditions, followed by adding at least one lactonemonomer or lactone prepolymer. The mixture is then subjected to thedesired conditions of temperature and time to copolymerize theprepolymer with the lactone monomers.

The polymers of the invention are prepared in accordance with methodscommonly employed in the field of synthetic polymers to produce avariety of useful products with valuable physical and chemicalproperties. The polymers are readily processed into pastes or can besolvent cast to yield films, coatings, microspheres and fibers withdifferent geometric shapes for the design of various medical implants,and may also be processed by compression molding and extrusion.

Polyurethanes, polyester urethanes, and polyamides prepared inaccordance with the present invention have average molecular weights ofabout 1500 to about 100,000 calculated by Gel Permeation Chromatography(GPC) relative to narrow molecular weight polystyrene standards.Preferred polyurethanes, polyester urethanes, and polyamides haveaverage molecular weights of about 1500 up to about 100,000 calculatedby Gel Permeation Chromatography (GPC) relative to narrow molecularweight polystyrene standards. Preferred Polyurethanes, polyesterurethanes, and polyamides have average molecular weights of about 1500up to about 40,000.

Processes for preparing polyamides of the invention are provided asfurther embodiments of the invention and are illustrated by thefollowing general method:

The diamines can also be reacted with diisocyanates (OCN—R—NCO) toprepare biodegradable polyureas.

Processes for preparing polyurethanes of the invention are provided asfurther embodiments of the invention and are illustrated by thefollowing general procedure:

These isocyanates can also be reacted with diamines (H₂N—R—NH₂) toprepare biodegradable polyureas

Chain Extenders: the nature of the chain extender group “R” in thepolymers of the invention is not very critical provided that the polymerof the invention possesses acceptable mechanical properties and releasekinetics for the selected therapeutic application. The chain extendergroup R is typically a divalent organic radical having a molecularweight of about 60 to about 5000. More preferably, R has a molecularweight of about 100 to about 1000, and may contain oxygen atoms, sulfuratoms and/or ester groups.

The chain extender group may be biologically inactive, or may itselfpossess biological activity. The chain extender group can also be apolyalkylene oxide, such as polyethylene oxide. The chain extender groupcan also be a polyester derived from at least one lactone monomer, suchas glycolide, lactide, p-dioxanone, trimethylenecarbonate, orcaprolactone. The chain extender group can also comprise otherfunctional groups (including hydroxy groups, amine groups, carboxylicacids, and the like) that can be used to modify the properties of thepolymer (e.g. for branching, for cross linking).

The mechanical properties, such as ultimate tensile strength, of thepolyurethanes of the present invention can in some cases be influencedprimarily by the polyol component as opposed to the hard segment as intypical segmented polyurethanes.

Suitable diols or polydiols for use in the present invention are diol ordiol repeating units with up to 8 carbon atoms. Examples of suitablediols include diols selected from 1,2-ethanediol (ethylene glycol),1,2-propanediol (propylene glycol), 1,3-propanediol, 1,4-butanediol,1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,4-cyclohexanediol, 1,8-octanediol and combinations thereof. Examplesof preferred polydiols include polydiols selected from polyethyleneglycol and polypropylene glycol with molecular weights of 500-10000.

Preferably, the polyurethane is of the type known as a segmentedpolyurethane, which is characterized by a formation of repeating softand hard blocks formed from a polyol component, a diisocyanate componentand an optional chain extender, and can occur in a linear, branched ornetworked form. The term chain extender is intended to refer to amulti-functional molecule which may be reacted with the previouslysynthesized pre-polymer to generate a high molecular weight polymer, apolyurethane for example. However, the formation of polyurethanes mayalso be carried out using such processes as a single step processinvolving reaction of the chain extender together with the diisocyanateand the polyol, without the formation of a prepolymer.

Preferably, the polyol component is selected according to thecomponent's toxicity, which is liberated when the polymer is brokendown. Two examples of appropriate polyols are polyethylene oxide andpolycaprolactone diol. Others may be suitable in some cases.

The constituents making up the polyurethane can be selected so as to bebiodegradable to substantially nontoxic constituents. The term‘substantially non-toxic’ is intended to refer to materials which whenpresent in the body are physically tolerated and, more specifically, donot cause appreciable cell death (cytotoxicity) or detrimentalalteration of normal cell function (such as a mutagenic response). Thiswould of course depend on where and how the material is applied.Detailed in vivo tests may be appropriate to determine the effect of thematerial on the neighboring cells.

Depending on the synthesis route selected, these cleavable sites may beregularly spaced along the length of the chain extender, thereby givingthe segmented polyurethane a biodegradability which is, by some measure,predictable. Biodegradability is influenced by a number of factors,including the number of susceptible sites, and crystallinity.

The hydrophilicity of the polymer, that is, the extent to which water isaccessible to the polymer matrix and the susceptible sites, may alsoinfluence the degradability. In those cases where the chain extender hasenzyme recognizable side groups, the access of water to the surface ofthe matrix should increase the rate at which the enzyme can catalyze thereaction between water and the hydrolyzable cleavage sites.

The number of cleavage sites also influences biodegradability. Thehigher the number of sites generally, the greater the rate ofdegradation. Preferably, the cleavable site is an ester site and, morepreferably, the cleavable ester site is adjacent one or more aminoacids. This provides segmented polyurethanes with cleavable sites in itschain extender that may be engineered to be recognizable by an enzyme.

In one embodiment, the diisocyanate is reacted with the polyol undersuitable conditions to form a prepolymer; the prepolymer is then reactedwith the chain extender, again under suitable conditions, to form thepolyurethane.

Alternatively, multi-functional components can be employed to produce across-linked network, and hence non-linear, segmented polyurethane. Thiscould be achieved by the use of a branched complex bearing more than twohydroxyl groups, such as for example a triol, for example. In anothercase, certain amino acids may also contribute to the formation of anetworked polymer. Lysine for example, having an amine group on its sidechain, may be reacted with such sites as a isocyanate group on thediisocyanate. Additionally, several lysines may be present in the aminoacid segment thereby providing potential bonding sites between eachcorresponding amine and another site such as an isocyanate group. Thus,such multi-functional components readily allow for the formation ofnonlinear segmented polyurethanes.

In one embodiment, substantially non-toxic degradable polyurethanes canbe formed from amino acids and substantially non-toxic diols, in such amanner, to be useful as biomaterials for a variety of applications suchas artificial skin, wound dressings, tissue engineering scaffolds andthe like. The polyurethane materials may be formed by melt or solventprocessing techniques such as dissolving the polymer into a solvent,pouring the mixture onto a flat sheet or into a mold and evaporating thesolvent, with the polymer remaining therein. Other melt processingtechniques may be available by melting a blank of polyurethane andmanipulating it into a shape as desired, including tubes or fibers. Aporous polyurethane may be formed in a number of ways, including theaddition of a gas (typically carbon dioxide) into the polymerizationreaction, and trapping the gas into the polymer structure.Alternatively, salt crystals can be added to the solvent polymer mixtureduring casting wherein the salt is not dissolved. The mixture may bedeposited into a dish causing the solvent to evaporate, with the saltmaterial being removed by subsequent washing with water.

One embodiment of the invention is directed to a polymer containing atleast one repeating unit of at least one of the compounds (1)-(30),above, wherein each X is independently selected from the groupconsisting of:

—CH₂COO— (glycolic acid moiety),—CH(CH₃)COO— (lactic acid moiety),—CH₂CH₂OCH₂COO— (dioxanone moiety), and—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);each X′ represents a member independently selected from the groupconsisting of:—OOCCH₂— (glycolic acid moiety);—OOCCH(CH₃)— (lactic acid moiety);—OOCCH₂OCH₂CH₂— (dioxanone moiety);—OOCCH₂CH₂CH₂CH₂CH₂— (caprolactone moiety);each X″ represents a member independently selected from the groupconsisting of:—OCH₂CO— (glycolic acid moiety);—OCH(CH₃)CO— (lactic acid moiety);—OCH₂CH₂OCH₂CO— (dioxanone moiety);—OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone moiety);each Y is independently selected from the group consisting of:—COCH₂O— (glycolic ester moiety);—COCH(CH₃)O— (lactic ester moiety);—COCH₂OCH₂ CH₂O— (dioxanone ester moiety); and—COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety); andeach Y′ represents a member independently selected from the groupconsisting of:—OCH₂CO— (glycolic ester moiety);—OCH(CH₃)CO— (lactic ester moiety);—OCH₂CH₂OCH₂CO— (dioxanone ester moiety);—OCH₂CH₂CH₂CH₂CH₂CO— (caprolactone ester moiety).

Further aspects of the invention comprise compositions and articlescomprising the above polymers.

In another embodiment, the present invention is directed to absorbablepolyurethanes comprising at least one cyclohexane-based compoundselected from structural formulas (8)-(15).

Accordingly, another aspect of the present invention is directed to anabsorbable polymer comprising at least one compound selected fromcyclohexane-based diamines (23)-(30).

Accordingly, yet another aspect of the present invention is directed tothe preparation of an absorbable polymer derived from at least onecompound selected from:

wherein each X represents a member independently selected from—CH₂COO— (glycolic acid moiety);—CH(CH₃)COO— (lactic acid moiety);—CH₂CH₂OCH₂COO— (dioxanone moiety);—CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);—(CH₂)_(y)COO— where y is one of the numbers 2,3,4 or 6-24 inclusive,and—(CH₂CH₂)_(z)′CH₂COO— where z′ is an integer between 2 and 24 inclusive;each Y represents a member independently selected from:—COCH₂O— (glycolic ester moiety);—COCH(CH₃)O— (lactic ester moiety);—COCH₂OCH₂ CH₂O— (dioxanone ester moiety);—COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);—CO(CH₂)_(m)O— where m is an integer between 2-4 and 6-24 inclusive, and—COCH₂O(CH₂CH₂O)_(n)— where n is an integer between 2 and 24, inclusive;each R′ is hydrogen, benzyl or an alkyl group, the alkyl group beingeither straight-chained or branched; and p is an integer between 1 and4, inclusive.

The polymers prepared by reacting the above amines or isocyanates withdiols, such as HO—R—OH, or with diacids, such as HOOC—R—COOH, caninclude, without limitation, polyurethanes, polyamides,polyesterurethanes and polyesteramides. The R group can be biologicallyinactive, or can itself possess biological activity. The R group canalso be a polyethylene oxide, a polyester derived from at least onelactone monomer, such as glycolide, lactide, p-dioxanone,trimethylenecarbonate, or caprolactone; other functional groups(including hydroxy groups, amine groups, carboxylic acids, etc), ordiols or polyols having up to 8 carbon atoms, such as 1,2-ethanediol(ethylene glycol), 1,2-propanediol (propylene glycol), 1,3-propanediol,1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,4-cyclohexanediol, 1,8-octanediol and combinations thereof. Examplesof preferred polydiols include polydiols selected from polyethyleneglycol and polypropylene glycol with molecular weights of 500-10000, allof which can modify the properties of the polymer (e.g. for branching orfor cross linking). Preferably, the Rn and R groups are selectedindependently to minimize the risk of toxicity when broken down orotherwise liberated.

A more preferred embodiment of the present invention comprisesabsorbable polymers containing at least one repeating unit having thestructure of any of formulas (I)-(IV). Another more preferred embodimentcomprises methods of preparing such units:

In another preferred embodiment, absorbable polymers are disclosedcontaining at least one repeating unit having the structure of any offormulas (V)-(VIII):

Still another aspect of the present invention comprises the preparationof absorbable polymers containing at least one repeating unit having thestructure of any of formulas (IX)-(XII):

Yet another aspect of the present invention comprises the preparation ofabsorbable polymers containing at least one repeating unit having thestructure of any of formulas (XIII)-(XVI):

Another aspect of the present invention comprises the preparation ofabsorbable polymers containing at least one repeating unit having thestructure of any of formulas (XVII)-(XX):

Still another aspect of the present invention comprises the preparationof absorbable polymers containing at least one repeating unit having thestructure of any of formulas (XXI)-(XXIV):

In yet another aspect of the present invention absorbable polymers aredescribed containing at least one repeating unit having the structure ofany of formulas (XXV)-(XXVIII):

Another aspect of the present invention comprises the preparation ofabsorbable polymers containing at least one repeating unit having thestructure of any of formulas (XXIX)-(XXXII):

Another aspect of the present invention is directed to a polymercomprising at least one repeating unit of at least one compound(I)-(XXXII). Further aspects of the invention comprise compositions andarticles comprising the above polymers.

Yet another aspect of the present invention is directed to methods andprocesses for preparing the biodegradable and bioabsorbable polymers ofthe invention from the monomers disclosed, vide supra, with or withoutthe inclusion of other monomers. The polymerization processes typicallyused for the formation of polyurethanes, polyamides, etc., arewell-known to those skilled in the art. Representative processes areprovided in U.S. Pat. No. 7,773,352, which is incorporated herein byreference in its entirety.

Monocaprolactone diisocyanate can be prepared according to Scheme 1.

where DSP is disodium phosphate, and TEA is triethylamine.

In yet another embodiment of the present invention, processes forpreparing polylactide diisocyanates are described following theprocedures depicted in Scheme 2.

In another embodiment of the present invention, processes for preparingdiethylene glycol diglycolate diisocyanate phenols are describedaccording to the procedures depicted in Scheme 3.

In another embodiment of the present invention, processes for preparingdiethylene glycol dilactate diisocyanate phenols;(4-isocyanato-phenoxy)-propionic acid2-{2-[2-(4-isocyanato-phenoxy)-propionyloxy]-ethoxy}-ethyl ester; aredescribed according to the procedure depicted in Scheme 4.

In another embodiment of the present invention, a process for preparingdiethylene glycol caprolactone diisocyanate phenols is describedaccording to the procedures depicted in Scheme 5.

In another embodiment of the present invention, processes for preparingdiethylene glycol caprolactone diisocyanate benzoic acid are describedaccording to the procedures depicted in Scheme 6.

Another aspect of the present invention focuses on the hydrophilicity ofthe polymer which may also influence the degradability, that is, theextent to which water is accessible to the polymer matrix. In thosecases where the chain extender has enzyme recognizable side groups, theaccess of the water to the surface of the matrix should increase therate at which an enzyme can catalyze the reaction between water and thehydrolyzable cleavage sites.

The number of cleavage sites also influences biodegradability. Thehigher the number of sites generally, the greater the rate ofdegradation. Preferably, the cleavable site is an ester site and, morepreferably, the cleavable ester site is adjacent to one or more aminoacids. This provides segmented polyurethanes with cleavable sites in itschain extender that may be arranged to be recognizable by enzymes. Inthis aspect of the invention, the rate of degradation is controlled toachieve the preferred therapeutic indication.

In one embodiment, the diisocyanate is reacted with a polyol, undersuitable conditions to form a prepolymer; and the prepolymer is thenreacted with the R group, again under suitable conditions, to form thepolyurethane.

In one embodiment, substantially non-toxic biodegradable polyurethanescan be formed from amino acids and substantially non-toxic diols, insuch a manner so as to be useful as biomaterials for a variety ofapplications such as artificial skin, wound dressings, tissueengineering scaffolds and the like. The polyurethane materials may beformed by solvent processing techniques such as dissolving the polymerinto a solvent, pouring the mixture onto a flat sheet or into a mold andevaporating the solvent, with the polymer remaining therein. Meltprocessing techniques can include, for example, melting a blank ofpolyurethane and manipulating it into shapes, such as tubes and fibers,as desired. A porous polyurethane is formed in a number of ways,including the addition of a gas (typically carbon dioxide) into thepolymerization reaction, and trapping the gas into the polymerstructure. Alternatively, salt crystals can be added to the solventpolymer mixture during casting wherein the salt is not dissolved. Themixture is deposited into a dish causing the solvent to evaporate, withthe salt material being removed by washing with water.

The polyurethane materials disclosed herein may be used in a number ofdifferent forms and in a range of applications, both in the biomedicalfield and others. The material can be fabricated by casting or othermolding techniques to form a substrate, which can be used alone orcombined with other substrates to form homogenous multi-layeredmaterials. Such multilayered homogeneous polyurethane materials may beformed with layers having different degrees of degradability. Suchsubstrates may range in thickness from about 1 micron to about 5millimeters for applications suitable for skin repair and the like, andmore particularly from about 10 microns to about 3.5 millimeters, andstill more particularly from about 50 microns to about 2 millimeters.The thinner the substrate, the more care is needed in handling it.

For bone regeneration and the like, the polyurethane material may rangein thickness from about 1 cm to about 5 cm or more, depending on thespecific application, including the dimensions of the bone beingregenerated. Preferably, the thickness is about 1 cm to about 5 cm.

In another aspect of the present invention the polyurethanes are of thesegmented variety which are bioabsorbable. In this aspect of theinvention the mechanical properties, such as ultimate tensile strength,of the polyurethanes can, in some cases, be influenced primarily by thepolyol as opposed to the hard segment, as for typical segmentedpolyurethanes. Preferably, such polyurethanes are of the type which ischaracterized by the formation of repeating soft and hard blocks formedfrom such intermediates as a polyol, a diisocyanate and a chainextender, R, and can occur in a linear, branched or networked form.Chain extenders may include multi-functional molecules which may bereacted with the previously synthesized pre-polymer to generate a highmolecular weight polyurethane for example. However, the formation ofpolyurethanes may also be carried out using such processes as a singlestep process involving reaction of the chain extender with thediisocyanate and the polyol, which process does not require theformation of a prepolymer.

In another aspect of the present invention, the polymers of the presentinvention may contain a cleavable site which is preferably an ester siteand, more preferably, the cleavable ester site is adjacent one or moreamino acids. This provides segmented polyurethanes with cleavable sitesin its chain extender, which sites may be arranged to be recognizable byenzymes.

In another embodiment of the present invention, the inventive polymerscan be used as a pharmaceutical carrier in a drug delivery matrix. Thematrix is formed by mixing the polymer with a therapeutic agent. A vastvariety of different therapeutic agents can be used in conjunction withthe polymers of the invention. In general, therapeutic agentsadministered via the pharmaceutical compositions of the inventioninclude, without limitation antiinfectives such as antibiotics andantiviral agents; analgesics and analgesic combinations; anorexics;antihelmintics; antiarthritics; anti-asthmatic agents; anticonvulsants;antidepressants; antidiuretic agents; antidiarrheals; antihist-amines;antiinflammatory agents; antimigraine preparations; antinauseants;antineo-plastics; antiparkinsonism drugs; antipruritics; antipsychotics;antipyretics, antispas-modics; anticholinergics; sympathomimetics;xanthine derivatives; cardiovascular preparations including calciumchannel blockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; para-sympatholytics;psychostimulants; sedatives; tranquilizers; and naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins orlipoproteins.

The drug delivery matrix may be administered in any suitable dosage formsuch as oral, parenteral, subcutaneously as an implant, vaginally or asa suppository. Matrix formulations containing polymers of the inventionis formulated by mixing one or more therapeutic agents with the polymer.The therapeutic agent may be present as a liquid, a finely dividedsolid, or any other appropriate physical form. Typically, the matrixwill include one or more additives, e.g., nontoxic auxiliary substancessuch as diluents, carriers, excipients, stabilizers or the like.However, the presence of such additives is entirely optional. Othersuitable additives may be formulated with the polymers of this inventionand pharmaceutically active agents or compounds, however, if water is tobe used it should be added immediately before administration.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001% to about 70%, more typically about 0.01%to about 50%, and most typically about 0.1% to about 20% by weight ofthe matrix.

The quantity and type of polymer incorporated into a parenteral dosageform will vary depending on the release profile desired and the amountof drug employed. The product may contain blends of polymers of thisinvention to provide the desired release profile or consistency to agiven formulation.

The polymers of this invention, upon contact with body fluids includingblood or the like, undergoes gradual degradation (mainly throughhydrolysis) with concomitant release of the dispersed drug for asustained or extended period (as compared to the release from anisotonic saline solution). This can result in prolonged delivery (overone to 2,000 hours, preferably two to 800 hours) of effective amounts(0.0001 mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form canbe administered as necessary depending on the subject being treated, theseverity of the affliction, the judgment of the prescribing physician,and the like.

Individual formulations of drugs and polymers of this invention may betested in appropriate in vitro and/or in vivo models to achieve thedesired drug release profiles. For example, a drug could be formulatedwith a polymer of this invention and orally administered to an animal.The drug release profile is monitored by appropriate means, such as bytaking blood samples at specific times and assaying the samples for drugconcentration. Following this or similar procedures, those skilled inthe art are able to formulate a variety of formulations having thedesired release profile.

The polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes of the invention may be formed into various articlesfor surgical and medical uses including, without limitation:

a. burn dressings,

b. hernia patches,

c. medicated dressings,

d. fascial substitutes,

e. gauze, fabric, sheet, felt or sponge for liver hemostasis,

f. gauze bandages,

g. arterial graft or substitutes,

h. bandages for skin surfaces,

i. suture knot clip,

j. orthopedic pins, clamps, screws, and plates,

k. clips (e.g., for vena cava),

l. staples,

m. hooks, buttons, and snaps,

n. bone substitutes (e.g., mandible prosthesis),

o. intrauterine devices (e.g., spermicidal devices),

p. draining or testing tubes or capillaries,

q. surgical instruments,

r. vascular implants or supports,

s. vertebral discs,

t. extracorporeal tubing for kidney and heart-lung machines,

u. artificial skin, and the like.

The polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes of the invention may be formed into surgical articlesusing any known technique, such as, for example, extrusion, moldingand/or solvent casting. The polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes may be used alone, blendedwith other bioabsorbable compositions, or in combination withnon-bioabsorbable components. A wide variety of surgical articles may bemanufactured from the polyurethanes, polyureas, polyamideurethanes,and/or polyureaurethanes described herein. These include but are notlimited to clips and other fasteners, staples, sutures, pins, screws,prosthetic devices, wound dressings or coverings, burn dressings orcoverings, drug delivery devices, anastomosis rings, stents, stentcoatings, films, scaffolds, polyurethane foams, reticulated foams andother implantable medical devices. Examples of medical implantabledevices include prosthetic devices, stents, sutures, staples, clips andother fasteners, screws, pins, films, meshes, drug delivery devices orsystems, anastomosis rings, surgical dressings and the like. In somepreferred embodiments, the surgical articles or components thereofinclude stents, stent coatings, wound coverings, burn coverings, foams,tissue engineering scaffolds, films, implantable medical devices, and/orcontrolled drug delivery systems, more preferably stents, stentcoatings, wound and/or burn coverings, and/or controlled deliverysystems. In certain other preferred embodiments, the surgical articlesor components thereof include sutures, ligatures, needle and suturecombinations, surgical clips, surgical staples, surgical prostheticdevices, textile structures, couplings, tubes, supports, screws, orpins. In certain preferred drug delivery systems, the systems comprise apolyurethane, polyurea, polyamideurethane, and/or polyureaurethane inadmixture with a biologically or pharmaceutically active agent.Non-limiting examples of polymeric carriers in such drug deliverysystems and/or pharmaceutical compositions include self-supportingfilms, hollow tubes, beads, and/or gels. Other preferred uses of thesurgical articles include their use as scaffolds for tissue engineeringcomprising a porous structure for the attachment and proliferation ofcells.

Preferably, the surgical and medical uses of the filaments, films, andmolded articles of the present invention include, but are notnecessarily limited to knitted products, woven or non-woven, and moldedproducts including, burn dressings, hernia patches, medicated dressings,facial substitutes, gauze, fabric, sheet, felt or sponge for liverhomeostasis, gauze bandages, arterial graft or substitutes, bandages forskin surfaces, suture knot clip, orthopedic pins, clamps, screws, andplates, clips (e.g., for vena cava), staples, hooks, buttons, and snaps,bone substitutes (e.g., mandible prosthesis), bone void fillers, bonecements, intrauterine devices (e.g., spermicidal devices), draining ortesting tubes or capillaries, surgical instruments, vascular implants orsupports, vertebral discs, extracorporeal tubing for kidney andheart-lung machines, artificial skin and others.

The polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes disclosed herein may also be used to fabricatedegradable containers and packaging materials which can degrade inlandfills in contrast to existing non-degradable materials which presentenvironmental concerns.

The polyurethane material is believed to be especially useful for use asa tissue engineering scaffold, i.e., as a structure for the growth orregeneration of tissue. Polyurethanes may lend themselves to such usessince enzyme-catalyzed degradation may in some cases occur concurrentlywith the migration or growth of cells into the material, while desirablydegrading in the process into its substantially non-toxic constituents.It is also possible, in some cases, that cells migrating into or locatedadjacent the matrix may themselves exude proteolytic enzymes that willmediate hydrolytic cleavage.

Such tissue engineering scaffolds may have applications in theregeneration of skin and other organs, bone, cartilage, ligaments,tendons, bladder and other tissues. The polyurethane material may alsobe useful in the production of sutures, which require good mechanicalstrength, as well as in the production of drug release matrices, in viewof their need for degradation to non-toxic materials. The polyurethanematerial may also be useful for non-biomedical applications, wheredegradability into substantially non-toxic constituents is an asset. Thepolyurethane material lends itself to sterilization by such techniquesas gamma radiation and ethylene oxide treatments.

Fibers made from the present polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes can be knitted or wovenwith other fibers, either bioabsorbable or non-bioabsorbable, to formmeshes or fabrics. Compositions including these polyurethanes,polyureas, polyamideurethanes, and/or polyureaurethanes may also be usedas bioabsorbable coatings for surgical devices.

Another aspect of the invention is directed to compositions containingthe polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes described herein which may be used to make reinforcedcomposites. Thus, for example, the polyurethane, polyurea,polyamideurethane, and/or polyureaurethane composition may form thematrix of the composite and may be reinforced with bioabsorbable ornon-bioabsorbable fibers or particles. Alternatively, a matrix of anybioabsorbable or non-bioabsorbable polymer composition may be reinforcedwith fibers or particulate material made from compositions containingthe polyurethanes, polyureas, polyamideurethanes, and/orpolyureaurethanes described herein.

In a further embodiment, the polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes described herein may beadmixed with a filler. The filler may be in any particulate form,including granulate or staple fibers. While any known filler may beused, hydroxyapatite, tricalcium phosphate, bioglass or otherbioceramics are the preferred fillers. Normally, from about 10 grams toabout 400 grams of filler are mixed with about 100 grams of polymer. Thefilled, cross-linked polymers are useful, for example, as moldingcompositions.

It is further contemplated that one or more medico-surgically usefulsubstances may be incorporated into compositions containing thepolyurethanes, polyureas, polyamideurethanes, and/or polyureaurethanesdescribed herein. Examples of such medico-surgically useful substancesinclude, for example and without limitation, those which accelerate orbeneficially modify the healing process when particles are applied to asurgical repair site. For example, articles made from compositionscontaining the presently disclosed polyurethanes, polyureas,polyamideurethanes, and/or polyureaurethanes may carry a therapeuticagent which will be deposited at the repair site. The therapeutic agentmay be chosen for its antimicrobial properties, capability for promotingrepair or reconstruction and/or new tissue growth. Antimicrobial agentssuch as broad spectrum antibiotics, for example and without limitation,gentamycin sulfate, erythromycin, or derivatized glycopeptides which areslowly released into the tissue, may be applied in this manner to aid incombating clinical and sub-clinical infections in a tissue repair site.To promote repair and/or tissue growth, one or several growth promotingfactors may be introduced into the articles, e.g., fibroblast growthfactor, bone growth factor, epidermal growth factor, platelet-derivedgrowth factor, macrophage-derived growth factor, alveolar-derived growthfactor, monocyte-derived growth factor, magainin, and the like. Examplesof therapeutic indications include, without limitation, glycerol withtissue or kidney plasminogen activator to cause thrombosis, superoxidedismutase to scavenge tissue-damaging free radicals, tumor necrosisfactor for cancer therapy or colony stimulating factor and interferon,interleukin-2 or other lymphokine to enhance the immune system.

Embodiments of the present invention are described with reference to thefollowing Examples, which are presented for illustrative purposes only,and are not intended to limit the scope of the invention in any way.

EXAMPLES

In a preferred embodiment, monocaprolactone diisocyanate compounds areprepared according to Scheme 1 described above, according to the stepsdescribed in examples 1-6.

Example 1 Synthesis of 6-(4-nitrophenoxy)-hexanoic acid methyl ester

To a mixture of 4-nitrophenol (150 g), Potassium carbonate (600 g),sodium iodide (10 g) in anhydrous acetone (2.1 liter) was added methyl6-bromohexanoate (156 g) and heated to reflux for 48 hours. Acetone wasdistilled and water (2 liter) was added. Crude6-(4-nitrophenoxy)-hexanoic acid methyl ester was filtered, dried andrecrystallised from a mixture of ethyl acetate and hexane (1:6) toobtain pure 6-(4-nitrophenoxy)-hexanoic acid methyl ester (130 g) as awhite powder with a melting point of 84.5.5-86.6° C. The product wascharacterized by ¹H NMR (CDCl₃) δ 1.56 (m, 2H, CH₂), 1.74 (m, 2H, CH₂),1.90 (s, 2H, CH₂), 3.68 (s, 3H, Ester), 4.06 (t, 2H, CH₂), 6.92 (d, 2H,Ar), 8.20 (d, 2H, Ar).

Similarly, substitution of 4-nitrocyclohexanol for 4-nitrophenolprovides the cyclohexane analog, according to procedures known to thoseskilled in the art.

Example 2 Synthesis of 6-(4-nitrophenoxy)-hexanoic acid

A mixture of 6-(4-nitrophenoxy)-hexanoic acid methyl ester (125 g) andconcentrated hydrochloride acid (1.2 L) was refluxed for 16 hours. Thereaction mixture cooled was to room temperature, filtered, dried andrecrystallised from a mixture of ethyl acetate and hexane (1:6) toobtain pure 6-(4-nitrophenoxy)-hexanoic acid (95 g) as a white powderwith a melting point of 104-107° C. The product was characterized by ¹HNMR (CDCl₃) δ 1.60 (m, 2H, CH₂), 1.76 (m, 2H, CH₂), 1.90 (m, 2H, CH₂),2.42 (t, 2H,CH₂), 4.04 (t, 2H₂OCH₂), 6.96 (d, 2H, Ar), 8.20 (d, 2H, Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 3 Synthesis of 6-(4-nitrophenoxy)-hexanoyl chloride

A mixture of 6-(4-nitrophenoxy)-hexanoic acid (20 g), thionyl chloride(40 ml) and dimethylformamide (0.5 ml) was refluxed for 5 hours. Excessthionyl chloride was distilled off under reduced pressure. Dry toluene(20 ml) added and solvent was removed under reduced pressure to obtain6-(4-nitrophenoxy)-hexanoyl chloride (20 grams) as light yellow oil.

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 4 Synthesis of 6-(4-nitrophenoxy)-hexanoic acid 4-nitrophenylester

To a mixture of 4-nitrophenol (10.8 g), triethylamine (22 ml) in ethylacetate (200 ml) at 0° C. was added 6-(4-nitrophenoxy)-hexanoyl chloride(20 g) dropwise, and the mixture was further stirred at room temperaturefor 16 hours. The reaction mixture was filtered to remove the salts,washed with 5% sodium bicarbonate, water and dried over anhydrous sodiumsulphate. The solvent was distilled off under vacuum and the purecompound was precipitated by adding cold methanol. After filtration anddrying, the compound was further recrystallized from a mixture ofchloroform and methanol (1:1) to give pure 6-(4-nitrophenoxy)-hexanoicacid 4-nitrophenyl ester (15 grams) as white powder with a melting pointof 73-76° C. The product was also characterized by ¹H NMR (CDCl₃) δ 1.60(m, 2H, CH₂), 1.85 (m, 6H, CH₂X 2), 2.70 (t, 2H, CH₂), 4.10 (t, 2H,CH₂), 6.95 (d, 2H, Ar), 7.30 (d, 2H, Ar), 8.25 (m, 4H, Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 5 Synthesis of 6-(4-aminophenoxy)-hexanoic acid 4-amino-phenylester

6-(4-nitrophenoxy)-hexanoic acid 4-nitrophenyl ester (20 g) wasdissolved in ethyl acetate (150 ml) in a pressure vessel. Palladium oncarbon (50% wet, 3 grams) was added as a catalyst and the mixture wasstirred under an atmosphere of hydrogen (5 Kg) for 1 hour. The catalystwas removed by filtration and the solvent was distilled off underreduced pressure, and the residue was triturated with cold hexane,filtered, and dried to give pure 6-(4-aminophenoxy)-hexanoic acid4-amino-phenyl ester (11 grams) as off-white powder with a melting pointof 99-101° C. The product was characterized by ¹H NMR (CDCl₃) δ 1.60 (m,2H, CH₂), 1.85 (m, 6H, CH₂ X 2), 2.55 (t, 2H, CH₂), 3.50 (bs, 4H, NH₂),3.90 (t, 2H, CH₂), 6.60 to 6.90 (m, 8H, Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Hydrolysis

0.5 g of the above diamine was subjected to hydrolysis in 50 ml of pH9.0 buffer at 100° C. The diamine was hydrolyzed in 3 hours.

Example 6 Synthesis of 6-(4-isocyanato-phenoxy)-hexanoic acid4-isocyanato-phenyl ester

6-(4-Aminophenoxy)-hexanoic acid 4-amino-phenyl ester (10 g) wasdissolved in dry 1,4-dioxane (160 ml) under nitrogen atmosphere, cooledto 10° C. and a solution of triphosgene (16 g) in dry 1,4-dioxane (40ml) was added in one lot. The mixture was heated slowly to 80° C. andmaintained at that temperature for 2 hours. The condenser was thenarranged for distillation and solvent was removed by distillation atatmospheric pressure until the volume of the reaction mixture wasreduced to approximately one third. Fresh dry 1,4-dioxane (50 ml) wasadded and distilled off under vacuum. The residue was re-evaporated twotimes from dry 1,4-dioxane to give crude6-(4-isocyanato-phenoxy)-hexanoic acid 4-isocyanato-phenyl ester. Crude6-(4-isocyanato-phenoxy)-hexanoic acid 4-isocyanato-phenyl ester wasdissolved in toluene (50 ml), treated with charcoal (3 grams), filteredand the toluene was distilled off under vacuum. The resulting residuewas triturated with cold hexane (75 ml) and filtered to give6-(4-isocyanato-phenoxy)-hexanoic acid 4-isocyanato-phenyl ester (5grams) as a white powder with a melting point of 62-64° C. The productwas characterized by ¹H NMR (CDCl₃) δ 1.60 (m, 2H, CH₂), 1.85 (m, 6H,CH₂ X 2), 2.70 (t, 2H, CH₂), 3.95 (t, 2H, CH₂), 6.80 (m, 2H, Ar), 7.10(m, 6H, Ar).

Similarly, substitution of thiophosgene for triphosgene provides theisothiocyanate analog, according to procedures known to those skilled inthe art. Also, preparation of the non-aromatic (reduced) analog isachieved by substitution of the corresponding cyclohexane analog,according to procedures known to those skilled in the art.

Hydrolysis of Diurethane

The diurethane of the above diisocyanate was prepared by reaction withmethanol. 0.5 g of the diurethane was subjected to hydrolysis in 50 mlof pH 9.0 buffer at 50° C. The diamine was hydrolyzed in 4 hours.

In another preferred embodiment, monolactate diisocyanate compounds andthe polymeric moieties obtained therefrom in Scheme 2, above, areprepared according to the steps described in examples 7-12.

Example 7 Synthesis of 2-(4-nitrophenoxy)-propionic acid methyl ester

Into a mixture of 4-nitrophenol (90 g), potassium carbonate (268 g),potassium iodide (10 g) and disodium phosphate (10 g) in anhydrousacetone (900 ml) was added methyl 2-chloro propionate (95 g). Thereaction mixture was stirred and refluxed for 24 hours. Acetone wasdistilled off and water (1.5 liter) was added to the reaction mixture.Crude 2-(4-nitrophenoxy)-propionic acid methyl ester was filtered, driedand recrystallised from methanol to obtain pure2-(4-nitrophenoxy)-propionic acid methyl ester (80 g) as a white powder.The product was characterized by ¹H NMR (CDCl₃) δ 1.70 (d, 3H, CH₃),3.78 (s, 3H, Ester), 4.85 (q, 1H, CH), 6.92 (d, 2H, Ar), 8.20 (d, 2H,Ar). The product has a melting point of 83-84° C.

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 8 Synthesis of 2-(4-nitrophenoxy)-propionic acid

A mixture of 2-(4-nitrophenoxy)-propionic acid methyl ester (80 g) andconcentrated hydrochloride acid (800 ml) was refluxed for 6 hours. Thereaction mixture was cooled to room temperature. The product wasfiltered off and dried to obtain pure 2-(4-nitrophenoxy)-propionic acid(55 g) as a white powder with a melting point of 139-140° C.

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 9 Synthesis of 2-(4-nitrophenoxy)-propionyl chloride

A mixture of 2-(4-nitrophenoxy)-propionic acid (40 g), thionyl chloride(80 ml) and dimethyl formamide (0.5 ml) was refluxed for 5 hours. Excessthionyl chloride was distilled off under reduced pressure. Dry toluene(20 ml) was added to the reaction mixture and solvent was removed underreduced pressure to obtain 2-(4-nitrophenoxy)-propionyl chloride (40 g)as light brown liquid.

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 10 Synthesis of 2-(4-nitrophenoxy)-propionic acid-4-nitrophenylester

To a mixture of 4-nitrophenol (21.8 g) and triethylamine (33 ml) inethyl acetate (360 ml) at 0° C. was added 2-(4-nitrophenoxy)-propionylchloride (36 g) dropwise, and the mixture was further stirred at roomtemperature for 1 hour. The reaction mixture was filtered to remove thesalts, washed with 5% sodium bicarbonate, followed by water, and theethyl acetate layer was dried over anhydrous sodium sulphate. Thesolvent was distilled off under vacuum and the compound was precipitatedby adding cold methanol. Filtration and drying gave pure2-(4-nitrophenoxy)-propionic acid-4-nitrophenyl ester (35 g) as whitepowder. The product had a melting point of 136-139° C., with a purity of99%. The product was characterized by ¹H NMR (CDCl₃) δ 1.85 (d, 3H,CH₃), 5.15 (q, 1H, CH), 7.05 (d, 2H, Ar), 7.28 (d, 2H, Ar), 8.30 (m, 4H,Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Example 11 Synthesis of 2-(4-aminophenoxy)-propionic acid 4-amino-phenylester

2-(4-nitrophenoxy)-propionic acid 4-nitrophenyl ester (30 grams, 90.28mmoles) was dissolved in ethyl acetate (600 ml) in a pressure vessel,palladium on carbon (50% wet, 6 grams) was added and the mixture stirredunder an atmosphere of Hydrogen (5 Kg) for 30 minutes. The catalyst wasremoved by filtration and the solvent distilled off under reducedpressure. The residue was triturated in cold diisopropyl ether, filteredand dried to give pure 2-(4-aminophenoxy)-propionic acid 4-amino-phenylester (15 grams) as off-white powder. The product has a melting point of109-111° C. The product was characterized by ¹H NMR (CDCl₃) δ 1.75 (d,3H, CH₃), 3.50 (bs, 2H, NH₂), 4.90 (q, 1H, CH), 6.65 (m, 4H, Ar), 6.80(m, 4H, Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Hydrolysis of Diamine

0.5 g of the above diamine compound was subjected to hydrolysis studiesin 50 ml of pH 9 buffer at 50° C. The diamine was completely hydrolyzedin 2 hours.

Example 12 Synthesis of 2-(4-isocyanato-phenoxy)-propionic acid4-isocyanato-phenyl ester

2-(4-Aminophenoxy)-propionic acid 4-amino-phenyl ester (6 g) wasdissolved in dry 1,4-dioxane (100 ml) under nitrogen atmosphere. Thereaction mixture was cooled to 10° C. and a solution of triphosgene (12g) in dry 1,4-dioxane (30 ml) was added. The mixture was heated slowlyto 100° C. and maintained at that temperature for 2 hours. The condenserwas then arranged for distillation and solvent was removed bydistillation under atmospheric pressure until the volume of the reactionmixture had been reduced to approximately one third. Fresh dry1,4-dioxane (30 ml) was added. The solvent was distilled off undervacuum. The residue was re-evaporated two times from dry 1,4-dioxane togive crude 2-(4-isocyanato-phenoxy)-propionic acid 4-isocyanato-phenylester. Crude 2-(4-isocyanato-phenoxy)-propionic acid 4-isocyanato-phenylester was dissolved in toluene (40 ml) and treated with charcoal (1 g).The solution was filtered off and the toluene was distilled off undervacuum to give 2-(4-isocyanato-phenoxy)-propionic acid4-isocyanato-phenyl ester (5 g) as a light yellow syrup. The product wascharacterized by ¹H NMR (CDCl₃) δ 1.75 (d, 3H, CH₃), 4.95 (q, 1H, CH),6.80 to 7.10 (m, 8H, Ar).

Similarly, substitution of thiophosgene for triphosgene provides theisothiocyanate analog. Also, preparation of the non-aromatic (reduced)analog is achieved by substitution of the corresponding cyclohexaneanalog, according to procedures known to those skilled in the art.

Hydrolysis of Diurethane

The diurethane of the above diisocyanate was prepared by reaction withmethanol. 0.5 g of the diurethane compound (a white powder having amelting point of 145-147° C.) was subjected to hydrolysis studies in 50ml of pH 9 buffer at 50° C. for 4 hours, followed by four hours at 80°C. The diurethane was completely hydrolyzed during the course of the 8hour period.

In yet another embodiment, diethylene glycol glycolate diisocyanatephenols; (4-isocyanato-Phenoxy)-Acetic acid2-[2-(4-isocyanato-Phenoxy)-acetoxy]-ethoxy)-ethyl ester, are describedin Scheme 3 and synthesized according to the steps of examples 13-16, asfollows.

Example 13 Synthesis of chloroacetic acid2-[2-(2-chloro-acetoxy)-ethoxy]-ethyl ester

In a 10-liter 4-neck round bottom flask equipped with a mechanicalstirrer and Dean-Stark apparatus was added a solution of diethyleneglycol (500 g), chloro acetic acid (980 g) and para-toluene sulphonicacid (25 g) in toluene (2.5 L). The solution was refluxed with stirringand azeotropic removal of water for 5 hours, and then cooled to roomtemperature. The toluene layer was washed with 5% sodium bicarbonatesolution (3×1000 ml) and water (3 L). The toluene layer was dried overanhydrous sodium sulphate, filtered, and distilled to obtainchloro-acetic acid 2-[2-(2-chloro-acetoxy)-ethoxy]-ethyl ester (1.1 Kg)as light yellow oil. The product was characterized by ¹H NMR (CDCl₃) δ3.75 (t, 2H, CH₂), 4.12 (s, 2H, CH₂), 4.36 (t, 2H, CH₂)

Example 14 Synthesis of (4-nitrophenoxy)-acetic acid2-{2-[2-(4-nitrophenoxy)-acetoxy]-ethoxy}-ethyl ester

To a mixture of 4-nitrophenol (966 g), potassium carbonate (4.26 Kg),sodium iodide (60 g), and disodium phosphate (60 g) in acetone (10 L)was added chloro-acetic acid 2-[2-(2-chloro-acetoxy)-ethoxy]-ethyl ester(1 Kg) and the mixture was stirred at reflux for 8 hours. Acetone wasdistilled off and cold water (250 ml) was added. The crude product wasfiltered off and slurried in methanol (10 L), re-filtered and dried togive (4-nitrophenoxy)-acetic acid2-{2-[2-(4-nitrophenoxy)-acetoxy]-ethoxy}-ethyl ester (1450 grams) as awhite powder with a melting point of 73-75° C. The product wascharacterized by ¹H NMR (CDCl₃) δ 3.62 (t, 2H, CH₂), 4.40 (t, 2H, CH₂),4.78 (s, 2H, CH₂), 6.95 (d, 2H, Ar), 8.15 (d, 2H, Ar).

Similarly, substitution of 4-nitrocyclohexanol for 4-nitrophenolprovides the cyclohexane analog, according to procedures known to thoseskilled in the art.

Example 15 Synthesis of (4-aminophenoxy)-acetic acid2-{2-[2-(4-aminophenoxy)-acetoxy]-ethoxy}-ethyl ester

(4-nitrophenoxy)-acetic acid2-{2-[2-(4-nitrophenoxy)-acetoxy]-ethoxy}-ethyl ester (600 g) wasdissolved in dimethylformamide (1.8 1) in a pressure vessel. RaneyNickel (800 grams) added and the mixture was stirred under an atmosphereof hydrogen (20 Kg) for 3 hours. The catalyst was removed by filtrationand the solution was added to cold water to precipitate the crudeproduct. The product was filtered off, slurried in methanol andre-filtered. The compound was dried to give pure (4-aminophenoxy)-aceticacid 2-{2-[2-(4-aminophenoxy)-acetoxy]-ethoxy}-ethyl ester (428 grams)as off-white powder with a melting point of 95-97° C. The product wascharacterized by ¹H NMR (CDCl₃) δ 3.10 (bs, 2H, NH₂), 3.70 (t, 2H, CH₂),4.35 (t, 2H, CH₂), 4.55 (s, 2H, CH₂), 6.60 (d, 2H, Ar), 6.75 (d, 2H,Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Hydrolysis Data of Diamine:

0.5 g of the above diamine was subjected to hydrolysis in 50 ml of pH9.0 buffer at 50° C. for 15 hours and then at 100° C. for 2 hours. Thediamine was completely hydrolyzed.

Example 16 Synthesis of (4-isocyanato-phenoxy)-acetic acid2-{2-[2-(4-isocyanato-phenoxy)-acetoxy]-ethoxy}-ethyl ester

(4-Aminophenoxy)-acetic acid2-{2-[2-(4-aminophenoxy)-acetoxy]-ethoxy}-ethyl ester (200 grams, 495mmoles) was dissolved in dry 1,4-dioxane (2000 ml) under nitrogenatmosphere and cooled to below 10° C. A solution of triphosgene (250grams, 842.45 mmoles) in dry 1,4-dioxane (600 ml) was added. The mixturewas heated slowly to 80° C. and maintained at that temperature for 2hours. The condenser was then arranged for distillation and the solventwas removed by distillation at atmospheric pressure until the volume ofthe reaction mixture had been reduced to approximately one third. Freshdry 1,4-dioxane (600 ml) was added and distilled off under vacuum. Theresidue was re-evaporated two times from dry 1,4-dioxane (1.2 L), thendry toluene (600 ml) and charcoal (20 g) were added. The solution wasfiltered hot, and toluene was distilled off under vacuum to give pure(4-isocyanato-phenoxy)-acetic acid2-{2-[2-(4-isocyanato-phenoxy)-acetoxy]-ethoxy}-ethyl ester (4.5 g) as alight yellow syrup. The product was characterized by ¹H NMR (CDCl₃) δ3.65 (t, 2H, CH₂), 4.35 (t, 2H, CH₂), 4.65 (s, 2H, CH₂), 6.75 (d, 2H,Ar), 7.00 (d, 2H, Ar).

Similarly, substitution of thiophosgene for triphosgene provides theisothiocyanate analog. Also, preparation of the non-aromatic (reduced)analog is achieved by substitution of the corresponding cyclohexaneanalog, according to procedures known to those skilled in the art.

Hydrolysis Data of Diurethane:

The diurethane of the above diisocyanate was prepared by reaction withmethanol.

5 grams of the diurethane was hydrolyzed in pH 9 buffer at 100° C. for 2hours, and after the hydrolysis a compound was isolated (1.5 grams), asa white powder with a melting point of 163-167° C., whose NMR spectrumindicated the formation of the following product, clearly resulting fromthe hydrolysis of the diethylene glycol linkage: ¹H NMR (CDCl₃) δ 3.75(s, 3H, CH₃), 4.65 (s, 2H, CH₂), 6.55 (bs, 1H, NH), 6.90 (d, 2H, Ar),7.30 (d, 2H, Ar).

In another embodiment, diethylene glycol dilactate diisocyanate phenols;(4-isocyanato-phenoxy)-propionic acid2-{2-[2-(4-isocyanato-phenoxy)-propionyloxy]-ethoxy}-ethyl ester; aredescribed in the Scheme 4 and synthesized according to the followingsteps of examples 17-21.

Example 17 Synthesis of 2-chloropropionic acid2-[2-(2-chloropropionyloxy)-ethoxy]-ethyl ester

In a 20 L glass reactor equipped with a Dean-Stark apparatus was added asolution of diethylene glycol (1500 g), 2-chloropropionic acid (3200 g)and para-toluene sulphonic acid (50 g) in toluene (5 L). The reactionmixture was refluxed for 5 hours with azeotropic removal of water, andthen cooled to room temperature. The toluene layer was washed with 5%sodium bicarbonate solution (4500 ml) and water (4 L). The toluene layerwas dried over anhydrous anhydrous sodium sulphate, and distilled toobtain 2-chloropropionic acid 2-[2-(2-chloropropionyloxy)-ethoxy]-ethylester (3.3 Kg) as light yellow oil. The product was characterized by ¹HNMR (CDCl₃) δ 1.65 (d, 3H, CH₃), 3.75 (t, 2H, CH₂), 4.40 (t, 2H, CH₂),4.48 (q, 1H, CH)

Example 18 Synthesis of (4-nitrophenoxy)-propionic acid2-{2-[2-(4-nitrophenoxy)-propionyloxy]-ethoxy}-ethyl ester

To a mixture of 4-nitrophenol (2.6 Kg), potassium carbonate (11.5 Kg),sodium iodide (100 g), and disodium phosphate (100 g) in acetone (30 L)was added 2-chloropropionic acid2-[2-(2-chloro-propionyloxy)-ethoxy]-ethyl ester (3 Kg). The reactionmixture was refluxed with stirring for 48 hours. The acetone wasdistilled off and cold water (25 L) was added. The crude product wasextracted into chloroform (15 L) and the chloroform extract was driedover anhydrous sodium sulphate. Chloroform was distilled off and thefinal product was precipitated from methanol. The solid was collected byfiltration, dried and recrystallised to give (4-nitrophenoxy)-propionicacid 2-{2-[2-(4-nitrophenoxy)-propionyloxy]-ethoxy}-ethyl ester (745grams) as a white powder. The product was characterized by ¹H NMR(CDCl₃) δ 1.65 (d, 3H, CH₃), 3.65 (t, 2H, CH₂), 4.30 (t, 2H, CH₂), 4.85(q, 1H, CH), 6.90 (d, 2H, Ar), 8.20 (d, 2H, Ar).

Similarly, substitution of 4-nitrocyclohexanol for 4-nitrophenolprovides the cyclohexane analog, according to procedures known to thoseskilled in the art.

Example 19 Synthesis of (4-aminophenoxy)-propionic acid2-{2-[2-(4-aminophenoxy)-propionyloxy]-ethoxy}-ethyl ester

(4-Nitrophenoxy)-propionic acid2-{2-[2-(4-nitrophenoxy)-propionyloxy]-ethoxy}-ethyl ester (300 g) wasdissolved in ethyl acetate (1.5 L) in a pressure vessel. Raney Nickelcatalyst (290 g) was added and the mixture was stirred under anatmosphere of hydrogen (10 Kg) for 4 hour. The catalyst was removed byfiltration and the solvent was distilled off under reduced pressure toobtain pure (4-aminophenoxy)-propionic acid2-{2-[2-(4-aminophenoxy)-propionyloxy]-ethoxy}-ethyl ester (254 g) as alight yellow syrup. The product was characterized by ¹H NMR (CDCl₃) δ1.60 (d, 3H, CH₃), 3.20 (bs, 2H, NH₂), 3.60 (t, 2H, CH₂), 4.25 (t, 2H,CH₂), 4.65 (q, 1H, CH), 6.60 (d, 2H, Ar), 6.75 (d, 2H, Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Hydrolysis Data of Diamine:

0.5 g of the above diamine was subjected to hydrolysis in 50 ml of pH9.0 buffer at 50° C. The diamine was hydrolyzed in 1.5 hours

Example 20 Synthesis of (4-isocyanato-phenoxy)-propionic acid2-{2-[2-(4-isocyanato-phenoxy)-propionyloxy]-ethoxy}-ethyl ester

(4-Aminophenoxy)-propionic acid2-{2-[2-(4-aminophenoxy)-propionyloxy]-ethoxy}-ethyl ester (217 g) wasdissolved in dry 1,4-dioxane (2 L) under nitrogen atmosphere. Thereaction mixture was cooled down to below 10° C. A solution oftriphosgene (253 g) in dry 1,4-dioxane (600 ml) was added. The mixturewas heated slowly to 80° C. and maintained at that temperature for 2hours. The condenser was then arranged for distillation and solventremoved by distillation under atmospheric pressure until the volume ofthe reaction mixture had been reduced to approximately one third. Freshdry 1,4-dioxane (600 ml) was added. Solvents were distilled off undervacuum. The residue was re-evaporated two times from dry 1,4-dioxane(1200 ml). Dry toluene (600 ml) and charcoal (50 g) was added. Thesolution was filtered hot and toluene was distilled off under vacuum togive pure (4-isocyanato-phenoxy)-propionic acid2-{2-[2-(4-isocyanato-phenoxy)-propionyloxy]-ethoxy}-ethyl ester (165 g)as a light yellow syrup. The product was characterized by ¹H NMR (CDCl₃)δ 1.65 (d, 3H, CH₃), 3.65 (t, 2H, CH₂), 4.30 (t, 2H, CH₂), 4.75 (q, 1H,CH), 6.80 (d, 2H, Ar), 7.00 (d, 2H, Ar).

Similarly, substitution of thiophosgene for triphosgene provides theisothiocyanate analog. Also, preparation of the non-aromatic (reduced)analog is achieved by substitution of the corresponding cyclohexaneanalog, according to procedures known to those skilled in the art.

Hydrolysis Data of Diurethane:

The diurethane of the above diisocyanate was prepared by reaction withmethanol.

0.5 g of the diurethane was subjected to hydrolysis in 50 ml of pH 9.0buffer at 50° C. The diurethane was hydrolyzed in 7 hours.

In yet another embodiment, diethylene glycol caprolactone diisocyanatephenol described in the Scheme 5 is synthesized according to thefollowing steps of examples 21-26.

Example 21 Synthesis of 6-bromohexanoic acid2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester

Into a 3-liter 4-neck round bottom flask equipped with a mechanicalstirrer was added a solution of diethylene glycol (100 g), 6-Bromohexanoic acid (386 g) and para-toluene sulphonic acid (5 g) in toluene(1000 ml). The solution was refluxed for 3 hours in a Dean-Starkapparatus with azeotropic removal of water. The solution was cooled toroom temperature and the toluene layer was washed with water (600 ml),5% sodium bicarbonate solution (1500 ml) and water (600 ml). The toluenelayer was dried over anhydrous sodium sulphate, filtered and distilledto obtain 6-bromohexanoic acid 2-[2-(6-bromohexanoyloxy)-ethoxy]-ethylester (400 g) as light yellow oil.

Example 22 Synthesis of 6-(4-nitrophenoxy)-hexanoic acid2-{2-[6-(4-nitrophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester

Into a mixture of 4-nitrophenol (60.5 g), potassium carbonate (180 g),potassium iodide (15 g), and disodium phosphate (15 g) in acetone (1000ml) was added 6-bromohexanoic acid2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester (100 g). The solution wasstirred at reflux for 24 hours. The acetone layer was distilled off andcold water (250 ml) was added. The crude product was extracted intochloroform and the chloroform extract was washed with 5% sodiumbicarbonate solution (800 ml) followed by water (600 ml). The chloroformlayer was dried over anhydrous sodium sulphate and distilled, and thefinal product was precipitated by adding diisopropyl ether. The crudeproduct was isolated by filtration and drying. The final product wasrecrystallized using a mixture of ethyl acetate and diisopropyl ether(1:3) to give pure 6-(4-nitrophenoxy)-hexanoic acid2-{2-[6-(4-nitrophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (100 grams) asa white powder. The product was characterized by ¹H NMR (CDCl₃) δ 1.50(m, 2H, CH₂), 1.70 (m, 2H, CH₂), 1.82 (m, 2H, CH₂), 2.38 (t, 2H, CH₂),3.74 (t, 2H, CH₂), 4.08 (t, 2H, CH₂), 4.26 (t, 2H, CH₂), 6.92 (d, 2H,Ar), 8.20 (d, 2H, Ar). The product has a melting point of 60-62° C.

Similarly, substitution of 4-nitrocyclohexanol for 4-nitrophenolprovides the cyclohexane analog, according to procedures known to thoseskilled in the art.

Example 23 Synthesis of 6-(4-aminophenoxy)-hexanoic acid2-{2-[6-(4-aminophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester

6-(4-Nitrophenoxy)-hexanoic acid2-{2-[6-(4-nitrophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (12 g) wasdissolved in ethyl acetate (200 ml) in a pressure vessel. 5% Palladiumon carbon (50% wet, 3 g) was added and the mixture was stirred under anatmosphere of hydrogen (5 Kg) for 1.5 hours. The catalyst was removed byfiltration, and the solvent was distilled off under reduced pressure toobtain the crude product which self crystallized over a period of timein the cold. The final product was slurried in diethyl ether, filteredand dried to give pure 6-(4-aminophenoxy)-hexanoic acid2-{2-[6-(4-aminophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (6 g) asoff-white powder. The final product was characterized by ¹H NMR (CDCl₃)δ 1.52 (m, 2H, CH₂), 1.65 (m, 4H, 2 X CH₂), 2.37 (t, 2H, CH₂), 3.20 (bs,2H, NH₂), 3.70 (t, 2H, CH₂), 3.88 (t, 2H, CH₂), 4.24 (t, 2H, CH₂), 6.64(d, 2H, Ar), 6.74 (d, 2H, Ar). The product has a melting point of 56-58°C.

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Hydrolysis Data of Diamine:

0.5 g of the above diamine was subjected to hydrolysis in 50 ml of pH9.0 buffer at 100° C. The diamine was hydrolyzed in 2 hours.

Example 24 Synthesis of 6-(4-isocyanato-phenoxy)-hexanoic acid2-{2-[6-(4-isocyanato-phenoxy)-hexanoyloxy]-ethoxy}-ethyl ester

6-(4-Aminophenoxy)-hexanoic acid2-{2-[6-(4-aminophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (5 g) wasdissolved in dry 1,4-dioxane (80 ml) under nitrogen atmosphere. Thesolution was cooled to below 10° C. A solution of triphosgene (4.8 g) indry 1,4-dioxane (20 ml) was added. The mixture was heated slowly to 80°C. and maintained at that temperature for 2 hours. The condenser wasthen arranged for distillation and the solvent was removed bydistillation at atmospheric pressure until the volume of the reactionmixture had been reduced to approximately one third. Fresh dry1,4-dioxane (25 ml) was added. The solvents were distilled off undervacuum. The residue was re-evaporated from dry 1,4-dioxane (50 ml) anddry toluene (30 ml) and charcoal (2 gram) was added. The solution wasfiltered hot. The toluene was distilled off under vacuum to give pure6-(4-isocyanatophenoxy)-hexanoic acid2-{2-[6-(4-isocyanatophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (4.5 g)as a light yellow oil. The product was characterized by ¹H NMR (CDCl₃) δ1.48 (m, 2H, CH₂), 1.68 (m, 2H, CH₂), 1.78 (m, 2H, CH₂), 2.37 (t, 2H,CH₂), 3.68 (t, 2H, CH₂), 3.92 (t, 2H, CH₂), 4.24 (t, 2H, CH₂), 6.78 (d,2H, Ar), 6.97 (d, 2H, Ar).

Similarly, substitution of thiophosgene for triphosgene provides theisothiocyanate analog. Also, preparation of the non-aromatic (reduced)analog is achieved by substitution of the corresponding cyclohexaneanalog, according to procedures known to those skilled in the art.

Hydrolysis Data of Diurethane:

The diurethane of the above diisocyanate was prepared by reaction withmethanol.

0.5 g of diurethane was subjected to hydrolysis in 50 ml of pH 9.0buffer at 100° C. The diamine was hydrolyzed in 8 hours.

In yet another embodiment, diethylene glycol caprolactone diisocyanatebenzoic acid described in the Scheme 6 is synthesized according to thefollowing steps of examples 25-28.

Example 25 Synthesis of 6-bromohexanoic acid2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester

Into a 3-liter 4-neck round bottom flask equipped with a mechanicalstirrer was added a solution of diethylene glycol (100 g), 6-bromohexanoic acid (386 g) and para-toluene sulphonic acid (5 g) in toluene(1000 ml). The solution was refluxed for 3 hours using a Dean-Starkapparatus with azeotropic removal of water. The solution was cooled toroom temperature. The toluene layer was washed with 5% sodiumbicarbonate solution (1500 ml) and water (1000 ml). The solution wasdried over anhydrous sodium sulphate and distilled to obtain6-bromohexanoic acid 2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester (400g) as light yellow oil.

Example 26 Synthesis of Dinitro Compound

Into a mixture of 4-nitrobenzoic acid (44 g) and triethylamine (76 ml)in dimethyl formamide (250 ml) was added 6-bromohexanoic acid2-[2-(6-bromohexanoyloxy)-ethoxy]-ethyl ester (50 g), and the mixturewas stirred at room temperature for 24 hours. The reaction mixture waspoured onto cold water (1000 ml). The crude product was extracted intochloroform, and the chloroform extract was washed with 5% sodiumbicarbonate solution (800 ml) followed by water (600 ml). The chloroformlayer was dried over anhydrous sodium sulphate. Chloroform was distilledoff and the crude product was purified by column chromatography usinghexane and ethyl acetate (80:20) as eluent to give pure dinitro compound(28 grams) as light yellow syrup. The product was characterized by ¹HNMR (CDCl₃) δ 1.50 (m, 2H, CH₂), 1.70 (m, 2H, CH₂), 1.82 (m, 2H, CH₂),2.38 (t, 2H, CH₂), 3.70 (t, 2H, CH₂), 4.24 (t, 2H, CH₂), 4.38 (t, 2H,CH₂), 8.20 (d, 2H, Ar), 8.28 (d, 2H, Ar).

Similarly, substitution of 4-nitrocyclohexanol for 4-nitrophenolprovides the cyclohexane analog, according to procedures known to thoseskilled in the art.

Example 27 Synthesis of Diamine

Dinitro compound (28 g) was dissolved in ethyl acetate (200 ml) in apressure vessel. 5% Palladium on carbon (50% wet, 5 g) was added ascatalyst and the mixture was stirred under an atmosphere of hydrogen (5Kg) for 3 hours. The catalyst was removed by filtration and ethylacetate was distilled off under reduced pressure to obtain the purediamine compound (24 g) as light yellow thick syrup. The product wascharacterized by ¹H NMR (CDCl₃) δ 1.48 (m, 2H, CH₂), 1.70 (m, 4H, 2 XCH₂), 2.35 (t, 2H, CH₂), 3.65 (t, 2H, CH₂), 4.10 (bs, 2H, NH₂), 4.25 (m,4H, 2 X CH₂), 6.60 (d, 2H, Ar), 7.85 (d, 2H, Ar).

Similarly, preparation of the non-aromatic (reduced) analog is achievedby substitution of the corresponding cyclohexane analog, according toprocedures known to those skilled in the art.

Hydrolysis Data of Diamine:

0.5 g of the above diamine compound was subjected to hydrolysis studiesin 50 ml of pH 9 buffer at 100° C. The diamine was completely hydrolyzedin 3 hours.

Example 28 Synthesis of Diisocyanate

The above diamine (10 g) was dissolved in dry 1,4-dioxane (160 ml) undera nitrogen atmosphere and cooled below 10° C. A solution of triphosgene(8.8 g) in dry 1,4-dioxane (40 ml) was added. The mixture was heatedslowly to 80° C. and maintained at that temperature for 2 hours. Thecondenser was then arranged for distillation and solvent was removed bydistillation under atmospheric pressure until the volume of the reactionmixture had been reduced to approximately one third. Fresh dry1,4-dioxane (300 ml) was added and the solvents were distilled off undervacuum. The residue was re-evaporated two times from dry 1,4-dioxane(600 ml) followed by dry toluene (50 ml). Charcoal (3 gram) was addedand the solution was filtered hot. The toluene was distilled off undervacuum to yield pure diisocyanate (9 g) as light yellow syrup. Theproduct was characterized by ¹H NMR (CDCl₃) δ 1.48 (m, 2H, CH₂), 1.66 to1.82 (m, 4H, 2 X CH₂), 2.37 (t, 2H, CH₂), 3.68 (t, 2H, CH₂), 4.24 (t,2H, CH₂), 4.34 (t, 2H, CH₂), 7.15 (d, 2H, Ar), 8.00 (d, 2H, Ar).

Similarly, substitution of thiophosgene for triphosgene provides theisothiocyanate analog. Also, preparation of the non-aromatic (reduced)analog is achieved by substitution of the corresponding cyclohexaneanalog, according to procedures known to those skilled in the art.

It will be understood that various modifications may be made to theembodiments disclosed herein. For example, the compositions inaccordance with this disclosure can be blended with other biocompatible,bioabsorbable or non-bioabsorbable materials. Therefore, the abovedescription should not be construed as limiting, but merely as anexemplification of preferred embodiments. Those skilled in the art mayenvision other modifications within the scope and spirit of the claimsprovided herein.

1-20. (canceled)
 21. A diisocyanate or diamine selected from the groupconsisting of the structures having formulas (8)-(15) and (23)-(30):

wherein: each X independently is selected from: —CH₂COO—; —CH(CH₃)COO—;—CH₂CH₂OCH₂COO—; —CH₂CH₂CH₂CH₂CH₂COO—; —(CH₂)_(y)COO—, where y is aninteger selected from 2, 3, 4, and 6-24 inclusive; and—(CH₂CH₂O)_(z)′CH₂COO—, where z′ is an integer between 2-24, inclusive;each X′ independently is selected from: —OOCCH₂—; —OOC(CH₃)CH—;—OOCCH₂OCH₂CH₂—; —OOCCH₂CH₂CH₂CH₂CH₂—; —OOC(CH₂)y-, where y is aninteger selected from 2, 3, 4, and 6-24 inclusive; and—OOCCH₂(OCH₂CH₂)z′- where z′ is an integer between 2-24, inclusive; eachX″ independently is selected from: —OCH₂CO—; —OCH(CH₃)CO—;—OCH₂CH₂OCH₂CO—; —OCH₂CH₂CH₂CH₂CH₂CO—; —O(CH₂)_(y)CO—, where y is aninteger selected from 2, 3, 4, and 6-24 inclusive; and—O(CH₂CH₂O)_(z)′CH₂CO—, where z′ is an integer between 2-24, inclusive;each Y independently is selected from: —COCH₂O—; —COCH(CH₃)O—;—COCH₂OCH₂CH₂O—; —COCH₂CH₂CH₂CH₂CH₂O—; —CO(CH₂)_(m)O—, where m is aninteger selected from 2, 3, 4, and 6-24 inclusive; and—COCH₂O(CH₂CH₂O)_(n)— where n is an integer between 2-24, inclusive;each Y′ independently is selected from: —OCH₂OC—; —O(CH₃)CHOC—;—OCH₂CH₂OCH₂OC—; —OCH₂CH₂CH₂CH₂CH₂OC—; —O(CH₂)_(m)OC— where m is aninteger selected from 2, 3, 4, and 6-24 inclusive; and—(OCH₂CH₂)_(n)OCH₂OC— where n is an integer between 2-24 inclusive; eachZ independently is selected from: —O—, —S—, and —NH—; each Rindependently is a phenylene group or a straight-chained or branchedalkylene group, these groups optionally contain one or more oxygenatoms, sulfur atoms, halogen atoms, ester groups, or aromatic groups;each Rn is independently selected from one or more members selectedfrom: H, alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid, and—NO₂; and, Rn is attached directly to the aliphatic ring or attachedthrough an alkylene chain.
 22. The diisocyanate or diamine of claim 21,wherein: each X independently is selected from: —CH₂COO—; —CH(CH₃)COO—;—CH₂CH₂OCH₂COO—; and, —CH₂CH₂CH₂CH₂CH₂COO—; each X′ independently isselected from: —OOCCH₂—; —OOC(CH₃)CH—; —OOCCH₂OCH₂CH₂—; and,—OOCCH₂CH₂CH₂CH₂CH₂—; each X″ independently is selected from: —OCH₂CO—;—OCH(CH₃)CO—; —OCH₂CH₂OCH₂CO—; and —OCH₂CH₂CH₂CH₂CH₂CO—; each Yindependently is selected from: —COCH₂O—; —COCH(CH₃)O—; —COCH₂OCH₂CH₂O—;and —COCH₂CH₂CH₂CH₂CH₂O—; each Y′ independently is selected from:—OCH₂CO—; —OCH(CH₃)CO—; —OCH₂CH₂OCH₂CO—; and —OCH₂CH₂CH₂CH₂CH₂CO—; eachZ independently is selected from: —O—, —S—, and —NH—; each R isindependently a straight-chained or branched alkylene containing 1-24carbon atoms and optionally containing one or more moieties selectedfrom: an oxygen atom, a sulfur atom, an ester group, an aromatic group,and a halogen atom; each p is independently an integer between 0 and 4,inclusive; and, each Rn is independently selected from one or moremembers selected from: H, alkoxy, benzyloxy, aldehyde, halogen,carboxylic acid, and —NO₂; Rn is attached directly to the aliphatic ringor attached through an alkylene chain.
 23. An absorbable polymerprepared from at least one diisocyanate or diamine compound of claim 21.24. The absorbable polymer of claim 23, comprising a polymer selectedfrom the group consisting of polyurethanes, polyamides, polyesterurethanes and polyesteramides.
 25. An article comprising a metal orpolymeric substrate having thereon a coating comprising: at least onepolymer according to claim 23, wherein said article contacts mammaliantissue.
 26. The article of claim 25, wherein said article is animplantable medical device.
 27. A controlled drug delivery systemcomprising: (1) one or more polymers according to claim 23, and (2) oneor more biologically or pharmacologically active agents.
 28. Thecontrolled drug delivery system of claim 27, wherein said one or morebiologically or pharmacologically active agents are physically embeddedor dispersed in a polymeric matrix comprising said one or more polymers.29. A tissue scaffold comprising one or more polymers according to claim23, wherein said tissue scaffold has a porous structure for theattachment and proliferation of cells, either in vitro or in vivo. 30.The polymer according to claim 23, wherein said polymer is furtherpolymerized on at least one end with polyesters of at least one lactonemonomer selected from the group consisting of glycolide, lactide,p-dioxanone, trimethylene carbonate and caprolactone.
 31. An articlecomprising a metal or polymeric substrate wherein said article is usedin (a) medicinal, medical device, therapeutic, consumer product,cosmetic or tissue engineering applications, or (b) wound healing and/orcontrolled drug delivery, and comprises a foam, or (c) sutures, bonehemostats, bone fillers, bone void fillers, bone cements, tissueadhesives, tissue sealants, adhesion prevention barriers, meshes, orfilters, or (d) stents, medical device coatings, pharmaceutical drugformulations, cosmetic packaging, pharmaceutical packaging, apparel,infusion devices, blood collection devices, tubes, skin care products ortransdermal drug delivery materials, and wherein said article comprisesat least one polymer according to claim
 23. 32. The article of claim31(b), wherein said foam comprises a reticulated foam.